L-aminodicarboxylic acid amides of alkoxyalkylamines

ABSTRACT

The present invention is directed to new sweeteners of the formula: ##STR1## wherein, A is H, alkyl containing 1-3 carbon atoms, hydroxyalkyl containing 1-3 carbon atoms, alkoxymethyl wherein the alkoxy group contains 1-3 carbon atoms, or CO 2  R in which R is alkyl containing 1-3 carbon atoms; 
     A&#39; is H or CH 3  ; 
     A and A&#39; when taken together with the carbon atom to which they are attached form a cycloalkyl containing 3-4 carbon atoms; 
     R 1  and R 2  are each a branched-chain alkyl containing 3-5 carbon atoms; and 
     m=0 or 1; 
     and food-acceptable salts thereof.

This is a division of application Ser. No. 738,202, filed May 24, 1985and now U.S. Pat. No. 4,603,011.

FIELD OF THE INVENTION

This invention relates to a novel group of compounds and moreparticularly to a novel group of compounds particularly well suited assweeteners in edible foodstuff.

DESCRIPTION OF THE PRIOR ART

Sweetness is one of the primary taste cravings of both animals andhumans. Thus, the utilization of sweetening agents in foods in order tosatisfy this sensory desire is well established.

Naturally occuring carbohydrate sweeteners such as sucrose, are stillthe most widely used sweetening agents. While thse naturally occurringcarbohydrates, i.e., sugars, generally fulfill the requirements of sweettaste, the abundant usage thereof does not occur without deleteriousconsequence, e.g., high caloric intake and nutritional imbalance. Infact, oftentimes the level of these sweeteners required in foodstuffs isfar greater than the level of the sweetener that is desired foreconomic, dietetic or other functional consideration.

In an attempt to eliminate the disadvantages concomitant with naturalsweeteners, considerable research and expense have been devoted to theproduction of artificial sweeteners, such as for example, saccharin,cyclamate, dihydrochalcone, aspartame, etc. While some of theseartificial sweeteners satisfy the requirements of sweet taste withoutcaloric input, and have met with considerable commercial success, theyare not, however, without their own inherent disadvantages. For example,many of these artificial sweeteners have the disadvantages of high cost,as well as delay in the perception of the sweet taste, persistentlingering of the sweet taste, and very objectionable bitter, metallicaftertaste when used in food products.

Since it is believed that many disadvantages of artificial sweeteners,particularly aftertaste, is a function of the concentration of thesweetener, it has been previously suggested that these effects could bereduced or eliminated by combining artificial sweeteners such assaccharin, with other ingredients such as aspartame or natural sugars,such as sorbitol, dextrose, maltose, etc. These combined products,however, have not been entirely satisfactory either. Some U.S. Patentswhich disclose sweetener mixtures include for example, U.S. Pat. No.4,228,198; U.S. Pat. No. 4,158,068; U.S. Pat. No. 4,154,862; and U.S.Pat. No. 3,717,477.

Accordingly, much work has continued in an attempt to develop andidentify compounds that have a sweet taste and which will satisfy theneed for better lower calorie sweeteners. Search continues forsweeteners that have intense sweetness, that is, deliver a sweet tasteat low use levels and which will also produce enough sweetness at lowlevels to act as sole sweetener for most sweetener applications.Furthermore, the sweeteners sought must have good temporal and sensoryqualities. Sweeteners with good temporal qualities produce atime-intensity sweetness response similar to natural sweeteners withoutlingering. Sweeteners with good sensory qualities lack undesirable offtastes and aftertaste. Furthermore, these compounds must be economicaland safe to use.

In U.S. Pat. No. 3,798,204, L-aspartyl-O-t-butyl-L-serine methyl esterand L-aspartyl-O-t-amyl-L-serine methyl ester are described as sweetcompounds having significant sweetness.

In U.S. Pat. No. 4,448,716 metal complex salts of dipeptide sweetnersare disclosed. In the background of this patent a generic formula isdescribed as an attempt to represent dipeptide sweeteners disclosed infive prior patents: U.S. Pat. No. 3,475,403; U.S. Pat. No. 3,492,131;Republic of South Africa Pat. No. 695,083 published July 10, 1969;Republic of South Africa Pat. No. 695,910 published Aug. 14, 1969. Thegeneral formula attempting to represent these patents is as follows:##STR2##

wherein R represents the lower alkyls, lower alkylaryls and cycloalkyls,n stands for integers 0 through 5, R₁ represents (a) phenyl group, (b)lower alkyls, (c) cycloalkyls, (d) R₂.

Where R₂ is hydroxy, lower alkoxy, lower alkyl, halogen, (e) (S(O)_(m)(lower alkyl) where m is 0, 1 or 2 and provided n is 1 or 2, (f) R₃.

Where R₃ represents an hydroxy or alkoxy and (g) single or doubleunsaturated cycloalkyls with up to eight carbons. These compounds alsoare not entirely satisfactory in producing a high quality sweetness orin producing a sweet response at lower levels of sweetener.

Dipeptides of aspartyl-cysteine and aspartylmethionine methyl esters aredisclosed by Brussel, Peer and Van der Heijden in Chemical Senses andFlavour, 4, 141-152 (1979) and in Z. Lebensm. Untersuch-Forsch., 159,337-343 (1975). The authors disclose the following dipeptides:

α-L-Asp-L-Cys(Me)-OMe

α-L-Asp-L-Cys(Et)-OMe

α-L-Asp-L-Cys(Pr)-OMe

α-L-Asp-L-Cys(i-Pr)-OMe

α-L-Asp-L-Cys(t-But)-OMe

α-L-Asp-L-Met-OMe

In U.S. Pat. No. 4,399,163 to Brennan et al., sweeteners having thefollowing formulas are disclosed: ##STR3## and physiologicallyacceptable cationic and acid addition salts thereof wherein

R^(a) is CH₂ OH or CH₂ OCH₃ ;

R is a branched member selected from the group consisting of fenchyl,diisopropylcarbinyl, d-methyl-t-butylcarbinyl, d-ethyl-t-butyl-carbinyl,2-methylthio-2,4-dimethylpentan-3-yl, di-t-butyl-carbinyl, ##STR4##

In a related patent, U.S. Pat. No. 4,411,925, Brennan, et al. disclosecompounds of the above general formula with R being defined hereinabove,except R^(a) is defined as methyl, ethyl, n-propyl or isopropyl.

U.S. Pat. No. 4,375,430 to Sklavounos discloses dipeptide sweetenerswhich are aromatic sulfonic acid salts of L-aspartyl-D-alaninoamides orL-aspartyl-D-serinamides.

European Patent Application No. 95772 to Tsau describe aspartyldipeptide sweeteners of the formula: ##STR5## wherein R' is alkyl of 1to 6 carbons, and R₂ is phenyl, phenylakylenyl or cyclohexylalkenyl,wherein the alkenyl group has 1 to 5 carbons. Closely related is U.S.Pat. No. 4,439,460 to Tsau, et al. which describes dipeptide sweetenersof the formula: ##STR6## wherein n is an integer from 0 to 5, and R₁ isan alkyl, alkylaryl or alicyclic radical. Similar such compounds aredescribed in many related patents, the major difference being thedefinition of R₂.

In U.S. Pat. No. 3,978,034 to Sheehan, et al., R₂ is defined ascycloalkenyl or phenyl. U.S. Pat. No. 3,695,898 to Hill defines R₂ as amono- or a di-unsaturated alicyclic radical. Haas, et al. in U.S. Pat.No. 4,029,701 define R₂ as phenyl, lower alkyl or substituted orunsubstituted cycloalkyl, cycloalkenyl or cycloalkadienyl, or S(O)_(m)lower alkyl provided that n is 1 or 2 and m is 0 or 2. Closely relatedare U.S. Pat. Nos. 4,448,716, 4,153,737, 4,031,258, 3,962,468,3,714,139, 3,642,491, and 3,795,746.

U.S. Pat. No. 3,803,223 to Mazur, et al. describe dipeptide sweetenersand anti-inflammatory agents having the formula: ##STR7## wherein R ishydrogen or a methyl radical and R' is a radical selected from the groupconsisting of alkyl, or ##STR8## wherein Alk is a lower alkyleneradical, X is hydrogen or hydroxy, and Y is a radical selected from thegroup consisting of cyclohexyl, naphthyl, furyl, pyridyl, indolyl,phenyl and phenoxy.

Goldkamp, et al. in U.S. Pat. No. 4,011,260 describe sweeteners of theformula: ##STR9## wherein R is hydrogen or a lower alkyl radical, Alk isa lower alkylene radical and R' is a carbocyclic radical. Closelyrelated is U.S. Pat. No. 3,442,431.

U.S. Pat. No. 4,423,029 to Rizzi describes sweeteners of the formula:##STR10## wherein R is C₄ -C₉ straight, branched or cyclic alkyl, andwherein carbons a, b and c have the (S) configuration.

European Patent Application No. 48,051 describes dipeptide sweeteners ofthe formula: ##STR11## wherein

M represents hydrogen, ammonium, alkali or alkaline earth,

R represents ##STR12##

R₁ represents methyl, ethyl, propyl,

R₂ represents --OH, or OCH₃,

* signifies an L-optical configuration for this atom.

German Patent Application No. 7259426 disclosesL-aspartyl-3-fenchylalanine methyl ester as a sweetening agent.

U.S. Pat. No. 3,971,822 to Chibata, et al., disclose sweeteners havingthe formula: ##STR13## wherein R' is hydrogen or hydroxy, R₂ is alkyl ofone to five carbon atoms, alkenyl of two to three carbon atoms,cycloalkyl of three to five carbon atoms or methyl cycloalkyl of four tosix carbon atoms and Y is alkylene of one to four carbon atoms.

U.S. Pat. No. 3,907,366 to Fujino, et al. disclosesL-aspartyl-aminomalonic acid alkyl fenchyl diester and itsphysiologically acceptable salts as useful sweeteners. U.S. Pat. No.3,959,245 disclose the 2-methyl cyclohexyl analog of the abovementionedpatent.

U.S. Pat. No. 3,920,626 discloses N-α L-aspartyl derivatives of loweralkyl esters of O-lower-alkanoyl-L-serine, β-alanine, γ-aminobutyricacid and D-β-aminobutyric acid as sweeteners.

Miyoshi, et al. in Bulletin of Chemical Society of Japan, 51, p.1433-1440 (1978) disclose compounds of the following formula assweeteners: ##STR14## wherein R' is H, CH₃, CO₂ CH₃, or benzyl and R₂ islower alkyl or unsubstituted or substituted cycloalkyl.

European Patent Application No. 128,654 describes gem-diaminoalkanesweeteners of the formula: ##STR15## wherein m is 0 or 1, R is loweralkyl (substituted or unsubstituted), R' is H or lower alkyl, and R" isa branched alkyl, alkylcycloalkyl, cycloalkyl, polycycloalkyl, phenyl,or alkyl-substituted phenyl, and physically acceptable salts thereof.

U.S. Pat. No. 3,801,563 to Nakajima, et al. disclose sweeteners of theformula: ##STR16## wherein R' is a branched or cyclic alkyl group of 3to 8 carbon atoms, R₂ is a lower alkyl group of 1 to 2 carbon atoms andn is a integer of 0 or 1.

European Patent Application No. 34,876 describes amides ofL-aspartyl-D-amino acid dipeptides of the formula: ##STR17## whereinR^(a) is methyl, ethyl, n-propyl or isopropyl and R is a branchedaliphatic, alicyclic or heterocyclic member which is branched at thealpha carbon atom and also branched again at one or both of the betacarbon atoms. These compounds are indicated to be of signficantsweetness.

In the Journal of Medicinal Chemistry, 1984, Vol. 27, No. 12, pp.1663-8, are described various sweetener dipeptide esters, includingL-aspartyl-α-aminocycloalkane methyl esters.

The various dipeptide esters of the prior art have been characterized aslacking significant stability at low pH values and/or thermal stability.These characterstics have limited the scope of use of these sweetenersin food products which are of low pH values or are prepared or served atelevated temperatures.

Accordingly, it is desired to find compounds that provide qualitysweetness when added to foodstuffs or pharmaceuticals at low levels andthus eliminate or greatly diminish the aforesaid disadvantagesassociated with prior art sweeteners.

SUMMARY OF THE INVENTION

The present new compounds are amides of certain α-aminodicarboxylicacids and alkoxyalkylamines which are low calorie sweeteners thatpossess a high order of sweetness with pleasing taste and higherstability at acid pH and elevated temperatures compared to knowndipeptide sweeteners.

This invention provides new sweetening compounds represented by theformula: ##STR18## wherein,

A is H, alkyl containing 1-3 carbon atoms, hydroxyalkyl containing 1-3carbon atoms, alkoxymethyl wherein the alkoxy group contains 1-3 carbonatoms, or CO₂ R in which R is alkyl containing 1-3 carbon atoms;

A' is H or CH₃ ;

A and A' when taken together with the carbon atom to which they areattached form a cycloalkyl containing 3-4 carbon atoms;

R₁ and R₂ are each a branched-chain alkyl containing 3-5 carbon atoms;and

m=0 or 1;

and food-acceptable salts thereof.

DESCRIPTION OF PREFERRED EMBODIMENTS

Preferred compounds include those wherein, R₁ and R₂ contain a total of6-8 carbon atoms, especially where at least one of R₁ and R₂ is atertiary alkyl. Of these the preferred are those wherein both R₁ and R₂are tertiary alkyl. Particularly preferred are the compounds in which R₁and R₂ are each tertiary butyl since these compounds, in presentexperience, appear to provide the highest sweetness in standardcomparison determinations with sucrose.

Alkyl groups illustrative of R₁ and R₂ include isopropyl, sec-butyl,sec-amyl, tertiary butyl and tertiary amyl. Of these, tertiary butyl ispreferred, as previously indicated, especially where R₁ and R₂ are eachtertiary butyl.

In those compounds in which A is CO₂ R, the preferred are those in whichR is methyl. Of the substituents representative of A, the preferred aremethyl, methoxymethyl and carbomethoxy in view of their high sweetnessand/or stability.

Particularly preferred compounds of this invention include:

N-L-aspartyl 0-[di-(t-butyl)methyl]serine methyl ester.

N-L-aspartyl 2-amino-3-[di-(t-butyl)methoxy]propane.

N-L-aspartyl 2-amino-2-methyl-3-[di-(t-butyl)methoxy]propane.

N-L-aspartyl 2-amino-1-methoxy-3-[di-(t-butyl)methoxy]propane.

N-L-aspartyl 1-amino-1-[di-(t-butyl)methoxymethyl]cyclopropane.

N-L-aspartyl 0-[di-(t-amyl)methyl]serine methyl ester.

N-L-aspartyl 2-amino-3-[di-(t-amyl)methoxy]propane.

N-L-aspartyl 2-amino-2-methyl-3-[di-(t-amyl)methoxy]propane.

N-L-aspartyl 2-amino-1-methoxy-3-[di-(t-amyl)methoxy]propane.

N-L-aspartyl 1-amino-1-[di-(t-amyl)methoxymethyl]cyclopropane.

N-L-aspartyl 0-[di-(isopropyl)methyl]serine methyl ester.

N-L-aspartyl 2-amino-3-[di-(isopropyl)methoxy]propane.

N-L-aspartyl 2-amino-2-methyl-1-[di-(isopropyl)methoxy]propane.

N-L-aspartyl 1-amino-1-[di-(isopropyl)methoxy]methyl cyclopropane.

N-L-aspartyl 2-amino-3-methoxy-1-[di-(isopropyl)methoxy]propane.

N-L-aspartyl 2-amino-1-[di-(isopropyl)methoxy]-3-hydroxy propane.

N-L-aspartyl 2-amino-1-[di-(isopropyl)methoxy]-3-methoxy propane.

These novel compounds are effective sweetness agents when used alone orin combination with other sweeteners in an ingesta, e.g., foodstuffs orpharmaceuticals. For example, other natural and/or artificial sweetenerswhich may be used with the novel compounds of the present inventioninclude sucrose, fructose, corn syrup solids, dextrose, xylitol,sorbitol, mannitol, acetosulfam, thaumatin, invert sugar, saccharin,thiophene saccharin, meta-aminobenzoic acid, metahydroxybenzoic acid,cyclamate, chlorosucrose, dihydrochalcone, hydrogenated glucose syrups,aspartame (L-aspartyl-L-phenylalanine methyl ester) and otherdipeptides, glycyrrhizin and stevioside and the like. These sweetenerswhen employed with the sweetness agents of the present invention, it isbelieved, could produce synergistic sweetness responses.

Furthermore, when the sweetness agents of the present invention areadded to ingesta, the sweetness agents may be added alone or withnontoxic carriers such as the abovementioned sweeteners or other foodingredients such as acidulants and natural and artificial gums. Typicalfoodstuffs, and pharmaceutical preparations, in which the sweetnessagents of the present invention may be used are, for example, beveragesincluding soft drinks, carbonated beverages, ready to mix beverages andthe like, infused foods (e.g. vegetables or fruits), sauces, condiments,salad dressings, juices, syrups, desserts, including puddings, gelatinand frozen desserts, like ice creams, sherbets, icings and flavoredfrozen desserts on sticks, confections, toothpaste, mouthwash, chewinggum, cereals, baked goods, intermediate moisture foods (e.g. dog food)and the like.

In order to achieve the effects of the present invention, the compoundsdescribed herein are generally added to the food product at a levelwhich is effective to perceive sweetness in the food stuff and suitablyis in an amount in the range of from about 0.0005 to 2% by weight basedon the consumed product. Greater amounts are operable but not practical.Preferred amounts are in the range of from about 0.001 to about 1% ofthe foodstuff. Generally, the sweetening effect provided by the presentcompounds are experienced over a wide pH range, e.g. 2 to 10 preferably3 to 7 and in buffered and unbuffered formulations.

It is desired that when the sweetness agents of this invention areemployed alone or in combination with another sweetner, the sweetener orcombination of sweeteners provide a sucrose equivalent in the range offrom about 2 weight percent to about 40 weight percent and morepreferably from about 3 weight percent to about 15 weight percent in thefoodstuff or pharmaceutical.

A taste procedure for determination of sweetness merely involves thedetermination of sucrose equivalency. Sucrose equivalence for sweetenersare readily determined. The amount of a sweetener that is equivalent toa given weight percent sucrose can be determined by having a panel oftasters taste solutions of a sweetener at known concentrations and matchits sweetness to standard solutions of sucrose.

In order to prepare compounds of the present invention several reactionschemes may be employed. In one reaction scheme compounds of the generalformula II (protected α-aminodicarboxylic acid) and III (etherifiedhydroxy amino compound) are condensed to form compounds of the generalformula IV. Subsequent removal of protecting groups A and B fromcompounds of general formula IV give the desired compounds of generalformula I. ##STR19##

In these, group Z is an amino protecting group, B is a carboxylprotecting group and the remaining groups have the same meaning aspreviously described. A variety of protecting groups known in the artmay be employed. Examples of many of these possible groups may be foundin "Protective Groups in Organic Synthesis" by T. W. Green, John Wileyand Sons, 1981. Among the preferred groups that may be employed arebenzyloxycarbonyl for Z and benzyl for B. When A includes a free hydroxygroup suitable protecting groups can be employed as known in the art.

Coupling of compounds with general formula II to compounds havinggeneral formula III employs established amide-forming techniques. Onesuch technique uses dicyclohexylcarbodiimide (DCC) as the couplingagent. The DCC method may be employed with or without additives such as4-dimethylaminopyridine or copper(II). The DCC coupling reactiongenerally proceeds at room temperature, however, it may be carried outfrom about 31 20° to 50° C. in variety of solvents inert to thereactants. Thus suitable solvents include, but are not limited to,N,N-dimethylformamide, methylene chloride, toluene and the like.Preferably the reaction is carried out under an inert atmosphere such asargon or nitrogen. Coupling usually is complete within 2 hours but maytake as long as 24 hours depending on reactants.

Various other amide-forming methods can be employed to prepare thedesired compounds using suitable derivatives of the free-carboxy groupin compounds of structure II, e.g., acid halide, mixed anhydride withacetic acid and similar derivatives. The following illustrates suchmethods using aspartic acid as the amino dicarboxylic acid.

One such method utilizes the reaction of N-protected aspartic anhydrideswith the selected amino compound of formula III. Thus compounds offormula III can be reacted directly in inert organic solvents withL-aspartic anhydride having its amino group protected by a formyl,carbobenzloxy, or p-methoxycarbobenzloxy group which is subsequentlyremoved after coupling to give compounds of general formula I. TheN-acyl-L-aspartic anhydrides are prepared by reacting the correspondingacids with acetic anhydride in amounts of 1.0-1.2 moles per mole of theN-acyl-L-aspartic acid at 0° to 60° C. in an inert solvent. TheN-acyl-L-aspartic anhydrides are reacted with preferably 1 to 2 moles ofcompounds of formula III in an organic solvent capable of dissolvingboth and inert to the same. Representative solvents are ethyl acetate,methyl propionate, tetrahydrofuran, dioxane, ethyl ether,N,N-dimethylformamide and benzene. The reaction proceeds smoothly at 0°to 30° C. The N-acyl group is removed after coupling by catalytichydrogenation with palladium on carbon or with HBr or HCl in aconventional manner. U.S. Pat. No. 3,879,372 discloses that thiscoupling method can also be performed in an aqueous solvent at atemperature of -10° to 50° C. and at a pH of 4-12.

Compounds of formula III are prepared by art-recognized procedures fromknown compounds or readily preparable intermediates. For example, thealkanol can be reacted with the appropriate nitroalkene in an inertsolvent. As in any organic reaction, solvents can be employed such asmethylene chloride, ether, tetrahydrofuran, dioxane, chloroform and thelike. The reaction is normally effected at 0° C., but temperaturesranging from -78° C. to 100° C. can be employed. Usually an inertatmosphere of nitrogen or argon is supplied. The nitro group of theformed product is then reduced by catalytic hydrogenation, e.g., H₂ /Pdor H₂ /Nickel.

Compound III can be prepared from the reaction of an alkanol and theappropriate N-protected alkyl aziridine in an inert solvent. Inertsolvents include methylene chloride, ether, tetrahydrofuran, dioxane,chloroform and the like. The reaction is normally effected at coldtemperatures, e.g., 0° C. but temperatures ranging from -78° C. to -100°C. can be employed. Usually an inert atmosphere of nitrogen or argon isemployed.

Compounds of general formula III may be synthesized from N-protectedethanolamine compounds by employing a variety of etherification methodsknown in the art. Some of these methods may be found in "ModernSynthetic Reactions", 2nd ed., by H. O. House, W. A. Benjamin, Inc.,1972; "Advanced Organic Chemistry", 2nd ed., by J. March McGraw-Hill,1977, and "Compendium of Organic Synthetic Methods", Vol. 1 and 2, by I.T. Harrison and S. Harrison, Wiley-Interscience, 1971 & 1974.

One etherification method is the base, or other catalyst, promotedreaction of N-protected ethanolamine compound with X--CHR₁ R₂, where Xis an organic leaving group such as halide, tosylate or mesylate. Anybase normally employed to deprotonate an alcohol may be used, such assodium hydride, sodium hydroxide, triethylamine, or diisopropylethylamine. Reaction temperatures are in the range of -78° to 100° C.and the reaction times vary from 2 to 48 hours. The reaction is carriedout in a solvent that will dissolve both reactants and is inert to bothas well. Solvents include, but are not limited to, diethyl ether,tetrahydrofurn, N,N-dimethylformamide, dimethylsulfoxide, and the like.Usually an inert atmosphere of nitrogen or argon is supplied.

Alternatively, a netural catalyst such as mercury (II) salts or nickel(II) 2,4-pentanedionate may be employed in this reaction. Thesereactions are also carried out in inert solvents at room temperature orabove. The intermediate formed in this reaction is deprotected to yieldcompounds of formula III.

A further method of etherification is the reaction of an N-protectedcompound of the formula

    NH.sub.2 --C(A)(A')--CH.sub.2 X

where X is halide, tosylate, mesylate or other leaving groups, with R₂R₁ CHOH using a base or other catalyst. Any base normally employed todeprotonate an alcohol may be used, including sodium hydride, sodiumhydroxide, triethylamine, or diisopropyl ethylamine. The reaction may berun either with or without additives, for example, copper salts.Reaction temperatures are in the range of -78° C. to 100° C., andreaction times vary from 2 to 48 hours. The reaction is carried out in asolvent that will dissolve both reactants and is inert to both. Solventsinclude, but are not limited to, diethyl ether, tetrahydrofuran,N,N-dimethylformamide, dimethylsulfoxide, and the like. Usually an inertatmosphere of nitorgen or argon is supplied.

Alternatively, a netural catalyst such as mercury (II) salts or nickel(II) 2,4-pentanedionate may be employed in this reaction. These are alsocarried out in inert solvents at room temperature or above. This productis then deprotected to yield compounds of general formula III.

The preparative procedures for formula III compounds also include anumber of alternative procedures known to those skilled in the art, e.g.etherification of the corresponding hydroxyethylamine:

    H.sub.2 N--C(A)(A')--CH.sub.2 OH

for example, employing a halide X--CH(R₁)(R₂) preferably in the presenceof a hydrogen halide acceptor, e.g. pyridine, triethylamine, and variousorganic amines known for this purpose.

Compounds in which A is hydroxymethyl can be prepared by reduction ofthe corresponding serine compound to convert the --CO₂ R group to CH₂ OHusing known procedures. The --CH₂ OH compounds can be alkylated to formthe corresponding alkoxymethyl compounds, e.g. using dimethylsulfate toform the methoxymethyl compound.

For compounds in which A and A' form a cycloalkyl group, similarprocedures can be used starting with ##STR20## a known compound. Forexample, CO₂ R can be converted to CH₂ OH by reduction procedures usinga variety of metal or alkylaluminum hydrides and, thereafter, the ethersformed by standard procedures.

In all cases, the amino group of formula III compounds is preferablyprotected in the intermediates using the usual reagents and theprotecting groups removed before condensation with formula II compounds.

With regard to the removal of protecting groups from compounds offormula IV and N-protected precursors of formula III, a number ofdeprotecting techniques are known in the art and can be utilized toadvantage depending on the nature of the protecting groups. Among suchtechniques is catalytic hydrogenation utilizing palladium on carbon ortransfer hydrogenation with 1,4-cyclohexadiene. Generally the reactionis carried at room temperature but may be conducted from 5° to 65° C.Usually the reaction is carried out in the presence of a suitablesolvent which may include, but are not limited to water, methanol,ethanol, dioxane, tetrahydrofuran, acetic acid, t-butyl alcohol,isopropanol or mixtures thereof. The reaction is usually run at apositive hydrogen pressure of 50 psi but can be conducted over the rangeof 20 to 250 psi. Reactions are generally quantitative taking 1 to 24hours for completion.

In any of the previous synthetic methods the desired products arepreferably recovered from reaction mixtures by crystallization.Alternatively, normal or reverse-phase chromatography may be utilized aswell as liquid/liquid extraction or other means.

The desired compounds of formula I are usually obtained in the free acidform; they may also be recovered as their physiologically acceptablesalts, i.e., the corresponding amino salts such as hydrochloride,sulfate, hydrosulfate, nitrate, hydrobromide, hydroiodide, phosphate orhydrophosphate; or the alkali metal salts such as the sodium, potassium,lithium, or the alkaline earth metal salts such as calcium or magnesium,as well as aluminum, zinc and like salts.

Conversion of the present new compounds of formula I into theirphysiologically acceptable salts is carried out by conventional means,as for example, bringing the compounds of formula I into contact with amineral acid, an alkali metal hydroxide, an alkali metal oxide orcarbonate or an alkaline earth metal hydroxide, oxide, carbonate orother complexed form.

These physiologically acceptable salts can also be utilized as sweetnessagents usually having increased solubility and stability over their freeforms.

It is known to those skilled in the art that the compounds of thepresent invention having asymmetric carbon atoms may exist in racemic oroptically active forms. All of these forms are contemplated within thescope of the invention.

An asymmetric carbon atom exists in those compounds where A and A'differ. Thus, optical isomers are possible in such compounds and thepresent compounds include such isomers. When A is CO₂ R, i.e. the serineesters, preference exists for the L-serine compounds which appear to besweeter than the D-compounds. In those compounds in which A is otherthan CO₂ R, and A' differs from A, the same chiral configuration as inL-serine is preferred. Mixtures of the optical isomers of course, can beemployed but compounds with the chiral configuration of L-serine arepreferred.

The preferred isomers can be prepared by pre-selecting intermediates ofappropriate configuration at the asymmetric center.

In addition to the aforesaid asymmetric center, a further such centerwill exist in those compounds in which R₁ and R₂ differ at theasterisked carbon atom:

The following examples further illustrate the invention:

EXAMPLE 1 N-(L-Aspartyl)-2-amino[di-(t-butyl)methoxy]propaneDi-t-butylmethanol

To a solution of trimethylacetaldehyde (5.12 g, 59.4 mmol) in anhydroustetrahydrofuran (15 ml) at -78° C. under an argon atmosphere is added40.9 ml of a solution of t-butyllithium in hexanes (1.6M, 65.4 mmol).The mixture is allowed to warm from -78° to room temperature over 2hours. The reaction is quenched with 25 ml of 1M hydrochloric acid andthe resulting mixture extracted with two 25 ml portions of ether. Thecombined ethereal extracts were washed with saturated sodium bicarbonatesolution and water, dried over magnesium sulfate, and the solventevaporated to yield a yellow oil (9.3 g) which is purified by vacuumdistillation to yield a colorless oil.

Method A:

Di-t-butylmethanol is added to a dry flask under argon at 0° C. Drytetrahydrofuran is added with a syringe. Sec-Butyl lithium (1.5M inHexanes) is added quickly in one portion and the contents of the flaskare stirred for one hour at room temperature. A 10 mM solution of18-crown-6-ether in acetonitrile is added with a syringe and the flaskcooled to 0° C. A tetrahydrofuran solution of 2-nitropropene is addedwith vigorous stirring over a 10 minute period. After completion of thereaction as judged by thin layer chromatography, it is quenched withsaturated ammonium chloride and extracted with ethyl acetate. Theorganic layer is dried over MgSO₄ and evaporated to yield 2-nitro1-[di-(t-butyl)methoxy]propane.

This product is dissolved in methanol and hydrogenated at 50 psi withRaney nickel T-1 as a catalyst. The reaction mixture is filtered throughCelite and evaporated to yield 2-amino 1-[di-(t-butyl)methoxy]propane.

Method B:

2-Methyl aziridine is dissolved in CH₂ Cl₂ and triethylamine under argonat 0° C. Benzylchloroformate is added and the contents of the flask areat room temperature overnight. The mixture is poured into 10% citricacid and is extracted with CHCl₃. The organic layer is washed withdilute aqueous NaHCO₃ and dried over MgSO₄. The solution is evaporatedto yield N-Cbz-2-methyl aziridine.

N-Cbz-2-Methyl aziridine and di-t-butylmethanol are dissolved in CH₂ Cl₂at 0° C. under argon. Boron trifluoride etherate is added and the flaskis stirred overnight. The contents are poured into saturated NaHCO₃ andare extracted with ethyl acetate. The organic layer is dried over MgSO₄and evaporated to yield N-Cbz-2-amino 1-[di-(t-butyl)methoxy]propane.

N-Cbz-2-Amino 1-[di-(t-butyl)methoxy]propane is dissolved in CH₃ OH andhydrogenated over 5% Pd/C in a Paar hydrogenation apparatus. When thereaction is complete the mixture is filtered through Celite andconcentrated to yield 2-amino 1-[di-(t-butyl)methoxy]propane.

To a magnetically stirred solution of 2-amino1-[di-(t-butyl)methoxy]propane in dry dimethylformamide at 0° C. underargon atmosphere is added N-Cbz-L-aspartic acid beta-benzyl esterfollowed by copper (II) chloride and dicyclohexyl cabodiimide. This isstirred for 18 hours, after which the reaction mixture is poured into0.1N HCl and extracted with ethyl acetate. The organic phase is washedwith saturated NaHCO₃ and then water, and dried over MgSO₄. Evaporationof the solvent yielded N-(N'-Cbz-L-aspartyl beta-benzyl ester) 2-amino1-[di-(t-butyl)methoxy]propane.

N-(N'-Cbz-L-aspartyl beta-benzyl ester)2-amino-1-[di-(t-butyl)methoxy]propane is dissolved in CH₃ OH andhydrogenated over 5% Pd/C in a Paar apparatus. Upon completion of thereaction the mixture is filtered and concentrated to yieldN-(L-aspartyl)-2-amino-1-[di-(t-butyl)methoxy]propane.

Similarly, by using the appropriate starting materials, the followingcompounds are also prepared:

N-(L-Aspartyl)-2-amino-1-[di-(t-amyl)methoxy]propane

N-(L-Aspartyl)-2-amino-1-[di-(isopropyl)methoxy]propane

N-(L-Aspartyl)-2-amino-1-[(isopropyl-t-butyl)methoxy]propane

EXAMPLE 2 N-(L-Aspartyl)-2-amino-2-methyl-1-[di-(t-butyl)methoxy]propane(1) Di-t-butylmethanol

To a solution of trimethylacetaldehyde (5.12 g, 59.4 mmol) in anhydroustetrahydrofuran (15 ml) at -78° C. under an argon atmosphere is added40.9 ml of a solution of t-butyllithium in hexanes (1.6M, 65.4 mmol).The mixture is allowed to warm from -78° to room temperature over 2hours. The reaction is quenched with 25 ml of 1M hydrochloric acic andthe resulting mixture extracted with two 25 ml portions of ether. Thecombined ethereal extracts were washed with saturated sodium bicarbonatesolution and water, dried over magnesium sulfate, and the solventevaporated to yield a yellow oil (9.3 g) which is purified by vacuumdistillation to yield a colorless oil.

(2) 2-amino-2-methyl-1-[di-(t-butyl)methoxy]propane

Method A:

Di-t-butylmethanol is added to a dry flask under argon at 0° C. Drytetrahydrofuran is added with a syringe. Sec-Butyl lithium (1.5M inHexanes) is added quickly in one portion and the contents of the flaskare stirred for one hour at room temperature. A 10 mM solution of18-crown-6-ether in acetonitrile is added with a syringe and the flaskcooled to 0° C. A tetrahydrofuran solution of 2-nitropropene is addedwith vigorous stirring over a 10 minute period. After completion of thereaction, as judged by thin layer chromatography, it is quenched withdimethyl sulfate, poured into saturated ammonium chloride and extractedwith ethyl acetate. The organic layer is dried over MgSO₄ and evaporatedto yield 2-nitro-2-methyl-1-[di-(t-butyl)methoxy]propane.

This product is dissolved in methanol and hydrogenated at 50 psi withRaney nickel T-1 as a catalyst. The reaction mixture is filtered throughCelite and evaporated to yield2-amino-2-methyl-1-[di-(t-butyl)methoxy]propane.

Method B:

2,2-Dimethyl aziridine is dissolved in CH₂ Cl₂ and triethylamine underargon at 0° C. Benzylchloroformate is added and the contents of theflask are stirred at room temperature overnight. The mixture is pouredinto 10% citric acid and extracted with CHCl₃. The organic layer iswashed with dilute aqueous NaHCO₃ and dried over MgSO₄. The solution isevaporated to yield N-Cbz-2,2-dimethylaziridine.

N-Cbz-2,2-Dimethyl aziridine and di-t-butylmethanol are dissolved in CH₂Cl₂ at 0° C. under argon. Boron trifluoride etherate is added and theflask is stirred overnight. The contents are poured into saturatedNaHCO₃ and extracted with ethyl acetate. The organic layer is dried overMgSO₄ and evaporated to yieldN-Cbz-2-amino-2-methyl-1-[di-(t-butyl)methoxy]propane.

N-Cbz-2-amino-2-methyl-1-[di-(t-butyl)methoxy]propane is dissolved inCH₃ OH and hydrogenated over 5% Pd/C in a Paar hydrogenation apparatus.When the reaction is complete the mixture is filtered through Celite andconcentrated to yield 2-amino-2-methyl-1-[di-(t-butyl)methoxy]propane.

Method C:

2-Methyl-2-amino-1-propanol is dissolved in saturated aqueous NaHCO₃ atroom temperature. Di-tert-butyl di-carbonate is added in tert-butanol.The contents are stirred overnight and then extracted with ethylacetate. The organic layer is dried over MgSO₄ and filtered. Thefiltrate is evaporated to give N-Boc-2-amino-2-methyl-1-propanol.

N-Boc-2-Amino-2-methyl-1-propanol is dissolved in triethylamine underargon at 0° C. Methanesulfonyl chloride is added and the mixture isstirred overnight. The solution is poured into 10% aqueous citric acidand extracted with ethyl acetate. The organic layer is dried over MgSO₄,filtered and evaporated to give N-Boc-2-amino-2-methyl-1-O-mesylate.

Di-t-butylmethanol is added to a dry flask under argon at 0° C. Drytetrahydrofuran is added with a syringe. Sec-Butyl lithium (1.5M inHexanes) is added quickly in one portion and the contents of the flaskare stirred for one hour at room temperature. A 10 mM solution of18-crown-6-ether in acetonitrile is added with a syringe and the flaskcooled to 0° C. A tetrahydrofuran solution ofN-Boc-2-amino-2-methyl-O-mesylate is added with vigorous stirring over a10 minute period. After completion of the reaction, as judged by thinlayer chromatography, it is quenched with dimethyl sulfate, poured intosaturated ammonium chloride and extracted with ethyl acetate. Theorganic layer is dried over MgSO₄ and evaporated to yieldN-Boc-2-amino-2-methyl-1-[di(t-butyl)methoxy]propane.

N-Boc-2-amino-2-methyl-1-[di-(t-butyl)methoxy]propane. propane isdissolved in trifluoroacetic acid and stirred overnight. The solution ispoured into water and neutralized with 20% aqueous KOH. The mixture isextracted with ethyl acetate, dried over MgSO₄, filtered and evaporatedto give 2-amino-2-methyl-1-[di-(t-butyl)methoxy]propane.

(3) Amide Formation

To a magnetically stirred solution of2-amino-2-methyl-1-[di(t-butyl)methoxy]propane in dry dimethylformamideat 0° C. under argon atmosphere is added N-Cbz-L-aspartic acidbeta-benzyl ester followed by copper (II) chloride anddicyclohexylcarbodiimide. This is stirred for 18 hours, after which thereaction mixture is poured into 0.1N HCl and extracted with ethylacetate. The organic phase is washed with saturated NaHCO₃ and thenwater, and dried over MgSO₄. Evaporation of the solvent yieldsN-(N'-Cbz-L-aspartyl beta-benzylester)-2-amino-2-methyl-1-[di-(t-butyl)methoxy]propane.

The product of the above paragraph is dissolved in CH₃ OH andhydrogenated over 5% Pd/C in a Paar apparatus. Upon completion of thereaction the mixture is filtered and concentrated to yieldN-(L-Aspartyl)-2-amino-2-methyl-1-[di-(t-butyl)methoxy]propane.

Similarly, by using the appropriate starting materials, the followingcompounds are also prepared:

N-(L-Aspartyl)-2-amino-2-methyl-1-[di-(t-amyl)methoxy]propane.

N-(L-Aspartyl)-2-amino-2-methyl-1-[di-(isopropyl)methoxy]propane.

N-(L-Aspartyl)-2-amino-2-methyl-1-[(isopropyl-t-butyl)methoxy]propane.

EXAMPLE 3 N-L-Aspartyl-2-amino-1-[(di-t-butyl)methoxy]methylcyclopropaneDi-t-butylmethanol

To a solution of trimethylacetaldehyde (5.12 g, 59.4 mmol) in anhydroustetrahydrofuran (15 ml) at -78° C. under an argon atmosphere is added40.9 ml of a solution of t-butyllithium in hexanes (1.6M, 65.4 mmol).The mixture is allowed to warm from -78° to room temperature over 2hours. The reaction is quenched with 25 ml of 1M hydrochloric acic andthe resulting mixture extracted with two 25 ml portions of ether. Thecombined ethereal extracts were washed with saturated sodium bicarbonatesolution and water, dried over magnesium sulfate, and the solventevaporated to yield a yellow oil (9.3 g) which is purified by vacuumdistillation to yield a colorless oil of Di-t-butylmethanol.

To a suspension of 1-amino-1-cyclopropane carboxylic acid in dry diethylether under argon at 0° C. is slowly added 1M borane in tetrahydrofuranwith vigorous stirring. The contents are stirred overnight and thenwater is added dropwise to destroy the remainder of the borane. Themixture is acidified with 2N HCl and then brought to approximately pH 11with 20% KOH and saturated with NaCl. The product is extracted withethyl acetate and the organic layer dried over MgSO₄. Filtration andevaporation of the solvent yields 1-amino-1-hydroxymethylcyclopropane.

1-Amino-1-hydroxymethylcyclopropane is dissolved in saturated aqueousNaHCO₃ at room temperature. Di-tert-butyl dicarbonate is added intert-butanol. The contents are stirred overnight and then extracted withethyl acetate. The organic layer is dried over MgSO₄ and filtered. Thefiltrate is evaporated to giveN-Boc-1-amino-1-hydroxymethylcyclopropane.

N-Boc-1-amino-1-hydroxymethylcyclopropane is dissolved in triethylamineunder argon at 0° C. Methanesulfonyl chloride is added with a syringeand the contents stirred at room temperature overnight. The solution ispoured into 10% aqueous citric acid and extracted with ethyl acetate.The organic layer is dried over MgSO₄, filtered and evaporated to giveN-Boc-1-amino-1-hydroxymethylcyclopropane-O-mesylate.

Di-t-butylmethanol is added to a dry flask under argon at 0° C. Drytetrahydrofuran is added with a syringe. Sec-Butyl lithium (1.5M inHexanes) is added quickly in one portion and the contents of the flaskare stirred for one hour at room temperature. A 10 mM solution of18-crown-6-ether in acetonitrile is added with a syringe and the flaskcooled to 0° C. A tetrahydrofuran solution ofN-Boc-1-amino-1-hydroxymethylcyclopropane-O-mesylate is added withvigorous stirring over a 10 minute period. After completion of thereaction, as judged by thin layer chromatography, it is quenched withdimethyl sulfate, poured into saturated ammonium chloride and extractedwith ethyl acetate. The organic layer is dried over MgSO₄ and evaporatedto yield N-Boc-1-amino 1-[di-(t-butyl)methoxy]methyl cyclopropane.

The above product is dissolved in trifluoroacetic acid and stirredovernight. The solution is poured into water and neutralized with 20%aqueous KOH. The mixture is extracted with ethyl acetate, dried overMgSO₄, filtered and evaporated to give1-[(di-t-butyl)methoxy-1-amino]methylcyclopropane.

To a magnetically stirred solution of1-amino-1-[di-(t-butyl)methoxy]methylcyclopropane in drydimethylformamide at 0° C. under argon atmosphere is addedN-Cbz-L-aspartyl acid beta-benzyl ester followed by cooper (II) chlorideand dicyclohexylcarbodiimide. This is stirred for 18 hours after whichthe reaction mixture is poured into 0.1 N HCL and extracted with ethylacetate. The organic phase is washed with saturated NaHCO₃ and thenwater, and dried over MgSO₄. Evaporation of the solvent yieldsN-(N'-Cbz-L-aspartyl beta-benzylester)-1-amino-1-[di-(t-butyl)methoxy]methylcyclopropane.

The above product is dissolved in absolute ethanol to give a 0.1Msolution. An equivalent weight of 10% palladium on carbon is added andthe solution is cooled in an ultra-sound ice bath. Cyclohexadiene (10equivalents) is added and sonication is begun. After the reaction iscomplete as judged by thin layer chromatography, the mixture is filteredthrough Celite with ethanol and evaporated to yield the final product.

Similarly, by using the appropriate alkanol, the following compounds arealso prepared:

N-(L-aspartyl)-1-amino-1-[di-(t-amyl)methoxy]methylcyclopropane.

N-(L-aspartyl)-1-amino-1-[di-(isopropyl)methoxy]methylcyclopropane.

N-(L-aspartyl)-1-amino-1-[(isopropyl-t-butyl)methoxy]methylcyclopropane.

EXAMPLE 4 N-(L-Aspartyl)-0-(di-t-butyl)methyl-L-serine methyl ester A.Di-t-butylmethanol

To a solution of trimethylacetaldehyde (5.12 g, 59.4 mmol) in anhydroustetrahydrofuran (15 ml) at -78° C. under an argon atmosphere is added40.9 ml of a solution of t-butyllithium in hexanes (1.6M, 65.4 mmol).The mixture is allowed to warm from -78° to room temperature over 2hours. The reaction is quenched with 25 ml of 1M hydrochloric acic andthe resulting mixture extracted with two 25 ml portions of ether. Thecombined ethereal extracts were washed with saturated sodium bicarbonatesolution and water, dried over magnesium sulfate, and the solventevaporated to yield a yellow oil (9.3 g) which is purified by vacuumdistillation to yield a colorless oil.

B. L-N-Triphenylmethyl serine methyl ester

A solution of L-serine methyl ester hydrochloride (100 g),triphenylmethylchloride (179.3 g) and triethylamine (197 ml) was stirredat 0° C. for 2 hours, then allowed to warm to room temperatureovernight. The solution was diluted with diethyl ether and then washedsuccessively with 10% aqueous citric acid and water, dried overmagnesium sulfate, and the solvent evaporated to yield the product (212g., 91%).

C. L-N-Triphenylmethyl-aziridine-2-carboxylic acid methyl ester

A mixture of compound B (212 g), methanesulfonyl chloride (45.6 ml), andpyridine (1.76 l) was stirred at 0° C., then allowed to warm slowly toroom temperature overnight. Ethyl acetate (1.5 l) was added, and theresulting solution washed with 10% aqueous citric acid and water, driedover magnesium sulfate and the solvent removed. The residual oil wasdissolved in tetrahydrofuran (2.5 l) and triethylamine (143 ml) wasadded. The mixture was heated at reflux overnight, then cooled and mostof the solvent was removed under vacuum. The residual oil was dissolvedin ethyl acetate (2 l) and the solution was washed successively with 10%aqueous citric acid saturated aqueous sodium bicarbonate, and water, andthen dried over magnesium sulfate, after which the solvent wasevaporated under vacuum. The residue was dissolved in hot methanol andthe product crystallized on cooling (115 g., 57%).

D. L-N-Benzyloxycarbonylaziridine-2-carboxylic acid methyl ester

To a cold solution (0° C.) of compound C (17.0 g) and methanol (100 ml)in dichloromethane (100 ml) was added concentrated sulfuric acid (5.0ml). The mixture was stirred at 0° C. for 10 min. Approximately half ofthe solvent was removed under vacuum, and the residue was dissolved inether. This was made basic with sodium bicarbonate and extracted withdichloromethane (3×25 ml). To these combined extracts was addedtriethylamine (4.36 g) and the solution was cooled to 0° C. Benzylchloroformate (7.80 g), was added, and the mixture was allowed to warmto room temperature overnight. The solution was then washed successivelywith 1M aqueous hydrochloric acid and saturated aqueous sodiumbicarbonate, dried over magnesium sulfate, and the solvent was removedunder vacuum to yield a brown oil (7.0 g). The product was purified bycolumn chromatography on silica gel (4:1 hexanes: ethyl acetate, eluent)to yield compound D, a pale yellow oil (3.44 g., 30%).

E. N-Benzyloxycarbonyl-0 -(di-t-butyl)methyl-L-serine methyl ester

To a solution of compound D (0.67 g) and di-t-butylmethanol (1.65 g) indichloromethane (20 ml) was added boron trifluoride diethyl etherate (15drops). The mixture is stirred at room temperature for 4 hours, thenwashed with water, dried over magnesium sulfate and the solvent isevaporated. The residue is purified by column chromatography (silicagel, 10:1, hexanes: ethyl acetate, eluent) to yield compound E (0.58 g).

F. O-di-t-butylmethyl-L-serine methyl ester

The product of E is dissolved in methanol in a Paar hydrogenation bottleand purged with argon. Palladium on carbon (5%) is added andhydrogenation carried out at 50 psi. After cessation of hydrogen uptake,the contents of the bottle are filtered through Celite and evaporated togive the product.

G.N-Benzyloxycarbonyl-α-L-aspartyl-β-benzylester-0-di-t-butylmethyl-L-serinemethyl ester

Compound F is coupled with N-benzyloxycarbonyl-L-aspartic acid-β-benzylester in dimethylformamide at 0° C. under argon in the presence ofCuCl₂, and dicyclohexylcarbodiimide. The mixture is stirred at roomtemperature for 3 hours and then poured into water and acidified with 2NHCl (pH 5). The product is extracted with ethyl acetate and the organicphase afforded an oil which is chromatographed on silica-gel with 2:1petroleum ether/ethyl acetate to give an oily product (370 mg).

H.

Product G is deprotected to the final product by hydrogenation (Paar)using Pd/C (5%) in methanol purged with argon. After cessation ofhydrogen uptake, the reaction mixture is filtered through Celite andevaporated to provide the unprotected product. Reverse phasechromatography on C₁₈ silica with 50% methanolic water gave purifiedproduct (110 mg), m. 165°-167° C.

Using the foregoing procedure, the corresponding O-di-t-amylmethyl,O-diisopropylmethyl and 1-isopropyl-1-t-butylmethyl serine ethers areprepared.

The following sensory evaluations were obtained by a panel of expertsusing known weight percent aqueous solutions of the above compoundmatched to sucrose standard solutions.

    ______________________________________                                        Concentration                                                                              Sucrose Equivalent                                                                           X-Sucrose                                         ______________________________________                                        0.005%       3.3%           660                                               0.010%       6.3%           630                                               0.025%       7.3%           308                                               ______________________________________                                    

It was further determined by the panel of experts that the sweetenerpossessed excellent temporal and sensory qualities.

EXAMPLE 5 N-(L-Aspartyl)-1-(2-amino-3-hydroxypropoxy)di-t-butylmethaneDi-t-butylmethanol

To a solution of trimethylacetaldehyde (5.12 g, 59.4 mmol) in anhydroustetrahydrofuran (15 ml) at -78° C. under an argon atmosphere is added40.9 ml of a solution of t-butyllithium in hexanes (1.6M, 65.4 mmol).The mixture is allowed to warm from -78° to room temperature over 2hours. The reaction is quenched with 25 ml of 1M hydrochloric acic andthe resulting mixture extracted with two 25 ml portions of ether. Thecombined ethereal extracts were washed with saturated sodium bicarbonatesolution and water, dried over magnesium sulfate, and the solventevaporated to yield a yellow oil (9.3 g) which is purified by vacuumdistillation to yield a colorless oil.

The product of Example 4 is dissolved in ether and is reduced withLiAlH₄ to give -(2-amino-3-hydroxypropoxy)di-t-butylmethane. To amagnetically stirred solution of this product in dry dimethyl formamideat 0° C. under argon atmosphere is added N-Cbz-L-aspartic acidbeta-benzyl ester, followed by copper (II) chloride anddicyclohexylcarbodiimide. This is stirred for 18 hours, after which thereaction mixture is poured into 0.1N HCl and extracted with ethylacetate. The organic phase is washed with saturated NaHCO₃ and thenwater and is dried over MgSO₄. The solvents evaporated off to giveN-(N'-Cbz-L-aspartyl beta-benzylester)-1-(2-amino-3-hydroxypropoxy)-di-t-butylmethane.

This product is dissolved in CH₃ OH and hydrogenated over 5% Pd/C in aPaar apparatus. Upon completion of the reaction, the mixture is filteredand concentrated to yield the final product.

Similarly, by utilizing the above procedure, and the appropriatealkanol, the corresponding di-t-amylmethane, diisopropylmethane and1-isopropyl-1-t-butylmethane compounds are prepared.

N-(L-Aspartyl)-1-(2-amino-3-methoxypropoxy)di-t-butylmethaneDi-t-butylmethanol

To a solution of trimethylacetaldehyde (5.12 g, 59.4 mmol) in anhydroustetrahydrofuran (15 ml) at -78° C. under an argon atmosphere is added40.9 ml of a solution of t-butyllithium in hexanes (1.6M, 65.4 mmol).The mixture is allowed to warm from -78° to room temperature over 2hours. The reaction is quenched with 25 ml of 1M hydrochloric acid andthe resulting mixture extracted with two 25 ml portions of ether. Thecombined ethereal extracts were washed with saturated sodium bicarbonatesolution and water, dried over magnesium sulfate, and the solventevaporated to yield a yellow oil (9.3 g) which is purified by vacuumdistillation to yield a colorless oil.

To a suspension of N-Benzyloxycarbonyl-0-di-t-butylmethyl-L-serinemethyl ester (prepared as in Example 4) in dry diethyl ether under argonat 0° C. is slowly added 1M borane in tetrahydrofuran with vigorousstirring. The contents are stirred overnight and then water is addeddropwise to destroy the remainder of the borane. The mixture isacidified with 2N HCl and then brought to approximately pH 11 with 20%KOH and saturated with NaCl. The product is extracted with ethyl acetateand the organic layer dried over MgSO₄ and filtered and the solvent isevaporated off.

The product of the preceding paragraph is dissolved in methylenechloride and methylated with dimethylsulfate to afford the1-(2-N-Boc-amino-3-methoxypropoxy)-di-t-butylmethane. This product isdissolved in methanol in a Paar hydrogenation bottle and purged withargon. Palladium on carbon (5%) is added and hydrogenation carried outat 50 psi. After cessation of hydrogen uptake, the contents of thebottle are filtered through celite and evaporated to give1-(2-amino-3-methoxypropoxy)di-t-butylmethane.

To a magnetically stirred solution of this product in dry dimethylformamide at 0° C. under argon atmosphere is added N-CbZ-L-aspartic acidbeta-benzyl ester followed by copper (II) chloride and dicyclohexylcarbodiimide. This is stirred for 18 hours, after which the reactionmixture is poured into 0.1N HCl and extracted with ethyl acetate. Theorganic phase is washed with saturated NaHCO₃, and then water and driedover the MgSO₄. The solvent is evaporated off to giveN-(N-CbZ-L-aspartyl-beta benzylester)-1-(2-amino-3-methoxypropoxy)di-t-butylmethane.

This product is dissolved in CH₃ OH and hydrogenated over 5% Pd/C in aParr apparatus. Upon completion of the reaction, the mixture is filteredand concentrated to yield the final product.

Similarly, by utilizing the above procedure and the appropriatecycloalkanol, the corresponding di-t-amylmethane, diisopropylmethane and1-isopropyl-1-t-butylmethane compounds are prepared.

What is claimed is:
 1. A compound represented by the formula: ##STR22##wherein, A is H, alkyl containing 1-3 carbon atoms, hydroxyalkylcontaining 1-3 carbon atoms, or alkoxymethyl wherein the alkoxy groupcontains 1-3 carbon atoms;A' is H or CH₃ ; A and A' when taken togetherwith the carbon atom to which they are attached form a cycloalkylcontaining 3-4 carbon atoms; R₁ and R₂ are each a branched-chain alkylcontaining 3-5 carbon atoms; and m=0 or 1; and food-acceptable saltsthereof.
 2. A compound according to claim 1 wherein at least one of R₁and R₂ is a tertiary alkyl.
 3. A compound according to claim 1 whereinR₁ and R₂ are each tertiary alkyl.
 4. A compound according to claim 1wherein R₁ and R₂ contain a total of 6-8 carbon atoms.
 5. A compoundaccording to claim 1 wherein R₁ and R₂ contain a total of 8 carbonatoms.
 6. A compound represented by the formula: ##STR23## wherein A isH, alkyl containing 1-3 carbon atoms, or alkoxymethyl wherein the alkoxygroup contains 1-3 carbon atoms;A' is H or CH₃ ; A and A' when takentogether with the carbon atom to which they are attached form acycloalkyl containing 3-4 carbon atoms; R₁ and R₂ are each abranched-chain alkyl containing 3-5 carbon atoms; and m=0 or 1; andfood-acceptable salts thereof.
 7. A compound according to claim 6wherein at least one of R₁ and R₂ is a tertiary alkyl.
 8. A compoundaccording to claim 6 wherein R₁ and R₂ are each tertiary alkyl.
 9. Acompound according to claim 6 wherein R₁ and R₂ contain a total of 6-8carbon atoms.
 10. A compound according to claim 6 wherein R₁ and R₂contain a total of 8 carbon atoms.
 11. A compound represented by theformula: ##STR24## wherein A is alkyl containing 1-3 carbon atoms;A' isH or CH₃ ; R₁ and R₂ are each a branched-chain alkyl containing 3-5carbon atoms; and m=0 or 1; and food-acceptable salts thereof.
 12. Acompound according to claim 11 wherein at least one of R₁ and R₂ is atertiary alkyl.
 13. A compound according to claim 11 wherein R₁ and R₂are each tertiary alkyl.
 14. A compound according to claim 11 wherein R₁and R₂ contain a total of 6-8 carbon atoms.
 15. A compound according toclaim 11 wherein R₁ and R₂ contain a total of 8 carbon atoms.
 16. Acompound represented by the formula: ##STR25## wherein A is alkoxymethylwherein the alkoxy group contains 1-3 carbon atomsA' is H or CH₃ ; R₁and R₂ are each a branched-chain alkyl containing 3-5 carbon atoms; andm=0 or 1; and food-acceptable salts thereof.
 17. A compound according toclaim 16 wherein at least one of R₁ and R₂ is a tertiary alkyl.
 18. Acompound according to claim 16 wherein R₁ and R₂ are each tertiaryalkyl.
 19. A compound according to claim 16 wherein R₁ and R₂ contain atotal of 6-8 carbon atoms.
 20. A compound according to claim 16 whereinR₁ and R₂ contain a total of 8 carbon atoms.
 21. A compound representedby the formula: ##STR26## wherein A and A' when taken together with thecarbon atom to which they are attached form a cycloalkyl containing 3-4carbon atoms;R₁ and R₂ are each branched-chain alkyl containing 3-5carbon atoms; and m=0 or 1; and food-acceptable salts thereof.
 22. Acompound according to claim 21 wherein at least one of R₁ and R₂ is atertiary alkyl.
 23. A compound according to claim 21 wherein R₁ and R₂are each tertiary alkyl.
 24. A compound according to claim 21 wherein R₁and R₂ contain a total of 6-8 carbon atoms.
 25. A compound according toclaim 21 wherein R₁ and R₂ contain a total of 8 carbon atoms.
 26. Thecompound according to claim 6 which is N-L-aspartyl2-amino-3-[di-(t-butyl)methoxy]propane.
 27. The compound according toclaim 6 which is N-L-aspartyl2-amino-2-methyl-3-[di-(t-butyl)methoxy]propane.
 28. The compoundaccording to claim 6 which is N-L-aspartyl2-amino-1-methoxy-3-[di-(t-butyl)methoxy]propane.
 29. The compoundaccording to claim 6 which is N-L-aspartyl2-amino-3-[di-(t-butyl)methoxy]propane.
 30. The compound according toclaim 6 which is N-L-aspartyl1-amino-1-[di-(t-butyl)methoxy]methylcyclopropane.
 31. The compoundaccording to claim 6 which is N-L-aspartyl2-amino-3-[di-(t-amyl)methoxy]propane.
 32. The compound according toclaim 6 which is N-L-aspartyl2-amino-2-methyl-3-[di-(t-amyl)methoxy]propane.
 33. The compoundaccording to claim 6 which is N-L-aspartyl2-amino-1-methoxy-3-[di-(t-amyl)methoxy]propane.
 34. The compoundaccording to claim 6 which is N-L-aspartyl2-amino-3-[di(t-amyl)methoxy]propane.
 35. The compound according toclaim 6 which is N-L-aspartyl1-amino-1-[di(t-amyl)methoxymethyl]cyclopropane.